We compared the prophylactic therapeutic effects of lithium versus carbamazepine (CBZ) for one year in a double-blind, randomized, crossover design followed by a third year of treatment with both drugs in combination in outpatients with manic-depressive illness. Non-responders have a fourth year on lithium plus valproate and a fifth year on triple mood stabilizer therapy. We have entered 54 patients (52 of whom have been randomized) and demonstrated the reliability, validity, and utility of the prospective life-charting methodology (NIMH-LCM). Thirteen of 44 (29.5%) failed lithium due to lack of efficacy, and two (4.5%) dropped out due to side effects. Thirteen of 45 (28.9%) failed CBZ due to lack of efficacy, and ten (22.2%) dropped out due to side effects (9 of the 10 had rash). Seven of 27 (25.9%) failed the combination. The percentage of patients who had marked or moderate improvement on the Clinical Global Index (CGI) scale was 33.4% on lithium, 31.5% on CBZ, and 51.8% on the combination. The treatment response varied across different drugs for individual patients, with four of the 14 CGI responders on lithium not responding on CBZ, four of the 11 CGI responders on CBZ not responding on lithium, and three of the 14 CGI responders on the combination not responding to either monotherapy. The duration of mania and number of manic episodes was found to differ significantly across the three drug states with lesser duration of mania on lithium and the combi- nation compared with CBZ. Substantial morbidity remained despite the use of antimanic or antidepressant adjuncts in 73.8% of patients on lithium, 74.3% on CBZ, and 70.4% on the combination. A past history of an increased duration of hospitalizations/year or number of mania hospi- talizations predicted a poor response to the combination. Rapid-cyclers did poorly on either monotherapy but much better on the combination. These data showing the high morbidity and dysfunction documented in a prospective fashion in bipolar patients receiving optimal management with either accepted mood stabilizer (alone or in combination) despite use of adjunctive treatments, suggest the importance of combination treatment (particularly for rapid cyclers), and indicate the need for the development of new drugs and treatment regimens for this serious, life- threatening, recurrent illness. A new randomized trial of lamotrigine vs. valproate is planned with additional randomized trials for manic and depressive episode breakthroughs. These include the collaborative randomized antidepressant comparison of sertraline, bupropion, venlafaxine in the 5-site NIMH-Stanley Foundation Treatment Outcome Network and comparison of the antimanic efficacy of clonazepam, trimipramine, and haloperidol.